The heparan sulfate co-receptor and the concentration of fibroblast growth factor-2 independently elicit different signa
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RESEARCH
The heparan sulfate co-receptor and the concentration of fibroblast growth factor-2 independently elicit different signalling patterns from the fibroblast growth factor receptor Research
Hongyan Zhu1,2, Laurence Duchesne1,3, Philip S Rudland1 and David G Fernig*1
Abstract Background: The fibroblast growth factor receptor (FGFR) interprets concentration gradients of FGF ligands and structural changes in the heparan sulfate (HS) co-receptor to generate different cellular responses. However, whether the FGFR generates different signals is not known. Results: We have previously shown in rat mammary fibroblasts that in cells deficient in sulfation, and so in HS coreceptor, FGF-2 can only stimulate a transient phosphorylation of p42/44MAPK and so cannot stimulate DNA synthesis. Here we demonstrate that this is because in the absence of HS, FGF-2 fails to stimulate the phosphorylation of the adaptor FGFR substrate 2 (FRS2). In cells possessing the HS co-receptor, FGF-2 elicits a bell-shaped dose response: optimal concentrations stimulate DNA synthesis, but supramaximal concentrations (≥ 100 ng/mL) have little effect. At optimal concentrations (300 pg/mL) FGF-2 stimulates a sustained dual phosphorylation of p42/44MAPK and tyrosine phosphorylation of FRS2. In contrast, 100 ng/mL FGF-2 only stimulates a transient early peak of p42/44MAPK phosphorylation and fails to stimulate appreciably the phosphorylation of FRS2 on tyrosine. Conclusions: These results suggest that the nature of the FGFR signal produced is determined by a combination of the HS co-receptor and the concentration of FGF ligand. Both the phosphorylation of the adaptor FRS2, the kinetics (sustained or transient) of phosphorylation of p42/44(MAPK) are varied, and so differing cellular responses are produced. Background Fibroblast growth factors (FGFs) constitute a family of structurally related proteins, which regulate many facets of cell behaviour, from embryonic patterning, to tissue repair and metabolism [1-3]. FGFs exert their effects on cells by interacting with a signalling receptor tyrosine kinase (FGFR) and a glycosaminoglycan co-receptor, usually heparan sulfate (HS) [4]. Assembly of the complex of FGF ligand, HS and FGFR leads to activation of the intracellular kinase of the receptor through autophosphorylation of two tyrosines in its activation loop, which results in the phosphorylation of other tyrosine residues in the intracellular domain of the receptor that serve as docking * Correspondence: [email protected] 1
School of Biological Sciences, Biosciences Building, Crown Street, University of Liverpool, Liverpool, L69 7ZB, UK
sites for SH2 and PTB domain containing proteins [1,5,6]. These include growth factor receptor binder-2 (GRB2) and FGFR substrate 2 (FRS2). FRS2 is a lipid-anchored docking protein, which serves as a major intracellular substrate of the FGFR kinase. Unlike GRB2, which binds via phosphotyrosines [7,8], FRS2 binds to the juxtamembrane region of FGFR via its phosphotyrosine-binding (PTB) domain independ
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